We wish to continue our study of genes needed for neuronal differentiation and function in the nematode Caenorhabditis elegans. Most of the research will center, as in the past, on the analysis of the development and activity of a set of six touch receptor neurons (the touch cells). Previous research under this grant has led to the identification of over 500 mutations that render the animal touch insensitive. These mutations define 17 genes needed for the generation, specification, maintenance, and function of the touch cells. Four of these genes and eight others that do not mutate to touch insensitivity act combinatorially in the development of the cells, allowing them to express cell-specific features and restricting their number to six. The remaining genes encode products that are needed for the function of the cells. We have developed a model in which the proteins encoded by twelve of these genes are components or modulators of the mechanosensory apparatus needed by the cells to sense touch. This is the first molecular model for a eukaryotic mechanical sense. In the upcoming grant period we wish to investigate how this combinatorial control specifies touch cell fate, uncover new touch-cell-specific genes, and test predictions of our model of mechanosensation. The specific aims of the proposal are: 1) to characterize combinatorial regulation of touch cell fate. 2) To identify and characterize new genes needed for touch cell development and function. 3) To continue the molecular genetic characterization of genes whose products are needed for mechanosensation. 4) To investigate the electrophysiological properties of a) wild-type and mutant touch cells in situ and b) touch-cell function proteins in Xenopus oocytes.